tbuckley/cabot-search huggingface dataset:
P039: HLA expression status and prognostic impact of B-cell content in patients with early-stage unfavorable Hodgkin lymphoma
Authors: Johanna Grund, Sarah Reinke, Annette Plütschow, Bastian Von Tresckow, Peter Borchmann, Andreas Engert, Paul J. Bröckelmann, Wolfram Klapper
Journal: HemaSphere (2022)

Figure 1: Kaplan-Meier Analysis of PFS according to B-cell content Introduction: Classical Hodgkin lymphoma (HL) is characterized by a complex, increasingly understood microenvironment which is considered crucial for survival and proliferation of the malignant Hodgkin and Reed-Sternberg cells (HRSC). HLA expression is a key component for immune cell interaction and thereby microenvironment composition. Additionally, we and others have shown that a low B-cell content is a negative prognostic factor in advanced-stage HL which can be assessed quantitatively by digital pathology using slides generated for diagnostic purposes (Jachimowicz 2021). Herein we aimed to assess HLA expression status and the prognostic relevance of B-cell content in early-stage unfavorable HL. Patients and Methods: We analyzed primary tumor biopsies of patients with newly diagnosed early-stage unfavorable HL either treated with 4xABVD or 2xBEACOPPesc followed by 2xABVD within the GHSG HD14 trial, each consolidated by 30Gy involved-field radiotherapy (von Tresckow 2012). Our project cohort was enriched for patients suffering from disease progression or relapse (20.2% vs 6.2% in the total HD14 population). Whole-slide image analysis of CD20 staining was performed using TissueStudio 64 (Definiens) to quantify the B-cell content. Immunohistochemistry for ß-2-Microglobulin (HLA-I) and HLA-DP (HLA-II) was scored by visual inspection on HRSC. Results: Major clinical variables such as sex, age, B-symptoms, GHSG risk factors and histological subtypes did not differ significantly between the project cohort (N=198) and HD14 trial population (N=1889). HLA-I and -II were expressed on HRSC in 13.3% and 49.1% of cases, respectively. Only 8.3% of cases showed positivity for both HLA-I and -II, while 45.8% were double-negative. Median B-cell content was lower in HLA-I negative (12.8% vs 18.5%, p=0.0168) and double-negative cases (11.5% vs 18.1% in double-positive cases, p=0.0392). A low B-cell content was associated with unfavorable outcome: 5-year PFS estimates are 70.6% and 83% for subjects with low (<=8%) or high (>8%) B-cell content (Figure 1, log-rank p=0.08). A stepwise multivariate analysis including type of treatment confirmed B-cell content as the only significant risk factor for PFS (p=0.0196). Conclusions: HLA expression is variable in early-stage unfavorable HL and associated with B-cell content. Similarly to advanced-stage HL, a low B-cell content measured by digital pathology of routinely available diagnostic slides is associated with unfavorable outcome.
T084: Treatment patterns and outcomes for Hodgkin’s Lymphoma (HL) patients (pts) aged 60 and older: a report from the Brazilian Prospective Hodgkin’s lymphoma Registry
Authors: Lilian Goveia, Nelson Castro, Carmino De Souza, Carolina Colaço. Villarim, Fabiola Traina, Carlos Sergio Chiattone, Monica Praxedes, Cristiana Solza, Leila Perobelli, Otavio Baiocchi, Rafael Gaiolla, Carla Boquimpani, Valeria Buccheri, Caroline Bonamin Sola, Roberta Oliveira De Paula E. Silva, Ana Carolina Ribas, Giovana Steffenello, Katia Pagnano, Andrea Soares, Samuel Souza Medina, Talita Silveira, Karin Zattar Cecyn, Leonardo Carvalho Palma, Mariana De Oliveira Marques, Nelson Spector, Irene Biasoli
Journal: HemaSphere (2022)

Introduction: Despite substantial progress in the treatment of HL, older pts remain an unmet treatment need. Methods: We sought to identify the treatment patterns and outcomes in HL pts ≥ 60 y/o included in the Brazilian HL registry. Results: A total of 141 pts with HIV negative classical HL aged ≥ 60, diagnosed from January 2009 to December 2018, were identified. Five pts were excluded, leaving 136 pts available for analysis. The median age was 66 years old (60–90), 49% were female, PS >1 in 21%, advanced stage in 72%, anemia in 38%, high-risk IPS score in 62% and nodular sclerosis (NS) in 49%. In comparison to younger pts, pts ≥ 60 y/o were more likely to have a high-risk IPS score (63% vs 38%, P<.0001), and histopathology other than NS (51% vs 23%, P<.0001). Also, older pts were more likely to have a lower socioeconomic status (SES, 47% vs 30%, P< .0001) and a lower educational level (25% vs 3%, P<.0001). Median follow-up was 45 months (0–144) for all pts and 64 months (14–144) for pts alive. ABVD was the first-line treatment in 96% of pts. Twenty-one pts (15%) died during the first treatment. In 18 (86%) of these pts, the cause of death was an infection or a complication of treatment. The 5-year PFS and 5-year OS were 55% and 59%. The 5-year PFS in localized and advanced disease were 72% and 47% (P=0.013). The 5-year OS in localized and advanced disease were 81% and 51% (P=0.013). Among 131 pts treated with ABVD, 5% presented cardiac toxicity, 11% lung toxicity and 12% severe infection. 65% of pts used bleomycin for > 2 cycles and 44% for > 4 cycles. In comparison with 2009–2014, there was a decrease in the use of bleomycin for > 2 cycles in 2015–2018 (88% x 45%, P<0.0001). The impact of (SES) on outcomes was studied in pts treated with ABVD. The fatality ratio during treatment was 9% and 21% for higher and lower SES (P=0.10). The 5-year PFS for higher and lower SES were 71% and 46% (P = .005), and the 5-year OS 72% and 55% (P = .027), respectively. After adjustments for potential confounders, lower SES remained independently associated with poorer survival (HR 2.22 [1.14–4.31] for OS and HR 2.84 [1.48–5.45] for PFS). Conclusion: Advanced stage and poor-risk pts predominated. Inferior outcomes are in part due to advanced disease at diagnosis and to an excess of deaths during treatment. SES is an independent factor for shorter survival. The use of bleomycin remains high, despite a substantial decrease in recent years.
P112: Phase II Trial of Brentuximab Vedotin plus ibrutinib in Relapsed/Refractory Hodgkin Lymphoma
Authors: Matthew Mei, Joycelynne Palmer, Kami Maddocks, Peter Martin, Ni-Chun Tsai, Eileen Smith, Leslie Popplewell, Saro Armenian, Geoffrey Shouse, Robert Chen, Larry Kwak, Steven T. Rosen, Stephen Forman, David Bond, Alex F. Herrera
Journal: HemaSphere (2022)

Background: Brentuximab vedotin (BV) is an antibody-drug conjugate and is highly effective in relapsed/refractory (r/r) Hodgkin lymphoma (HL). Although most patients respond to BV, only a minority will obtain a complete response (CR), and almost all patients eventually progress. Ibrutinib (Ibr) is a Bruton tyrosine kinase (BTK) inhibitor active in multiple subtypes of non-Hodgkin lymphoma. Limited data exist regarding its use in HL, but malignant Reed-Sternberg cells can express BTK. Ibr also inhibits IL-2-inducible kinase (ITK) with Th1 based responses which may promote immunogenic cell death in combination with BV. As we previously observed preclinical synergy between Ibr and BV, we hypothesized Ibr may enhance the antitumor activity of BV in HL. We conducted a phase II trial of Ibr plus BV in patients with r/r HL and report here the final primary analysis of safety and efficacy. Methods: This was a multicenter phase II trial with a 6 patient safety lead-in cohort of BV and Ibr in patients with r/r HL. Eligibility included age > 15 years with r/r HL after at least one prior line of therapy. Prior BV was allowed if patients were not refractory. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and Ibr 560 mg oral daily (420 mg in the lead-in cohort). The primary endpoint was CR rate according to Lugano 2014. Secondary endpoints included toxicity, overall response rate (ORR), and duration of response (DOR). Results: 39 patients were enrolled; 67% were male and median age was 33. At initial diagnosis 40% had stage III-IV disease and 38% had extranodal disease. 51% were refractory to most recent therapy, and 21% had prior BV. Of 36 evaluable patients, CR rate was 33%, ORR 64%, and median DOR 25.5 months (range); median number of cycles received was 5. Most common adverse events of any grade were nausea (67%), diarrhea (59%), peripheral neuropathy (62%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). 6 (%) patients experienced unacceptable toxicity, defined as Gr 3/4 non-hematologic toxicity or non-resolving Gr 3/4 hematologic toxicity including one patient who died of sepsis during cycle 1. Discussion: The combination of BV and Ibr had similar efficacy to BV monotherapy in patients with r/r HL, but with additional toxicity compared to BV alone.
P044: PIM kinases support protumoral and immunosuppressive phenotype and functions of macrophages in classical Hodgkin Lymphoma
Authors: Maciej Szydłowski, Filip Garbicz, Ewa Kurtz, Michał Pawlak, Patryk Górniak, Anna Szumera-Ciećkiewicz, Kamil Sokół., Monika Kawecka, Daria Owczarek, Beata Puton, Monika Prochorec-Sobieszek, Daniela Bellarosa, Michał Kurlapski, Jan Maciej Zaucha, Przemysław Juszczyński
Journal: HemaSphere (2022)

Increased abundance of tumor-associated macrophages (TAMs) predicts shortened survival of patients with classical Hodgkin lymphoma (cHL). TAMs in cHL might support growth of the malignant, Reed-Sternberg (RS) cells and due to expression of PD-L1, contribute to T-cell exhaustion. In our previous studies, we identified almost universal expression of PIM-1/2/3 kinases (PIMs) in RS cells, but also noted that they are expressed in TAMs. In RS cells, PIMs support malignant cells survival and immune privilege. However, their role in the biology of cHL-TAMs remains to be explored. Herein, using an in vitro model of cHL-TAMs (RS-conditioned macrophages, RS-M) we characterize consequences of PIM inhibition for phenotype and functions of TAMs in cHL. THP1 cells and donor-derived monocytes were differentiated into macrophages (MΦ-0) using PMA and CSF-1 respectively. MΦ-0 were next cocultured with L428 or L1236 RS cells under conditions prohibiting direct contacts. Compared to MΦ-0, RS-M exhibited elevated expression of PIMs and genes involved in chemotaxis/immunomodulation (CCLs: 2, 5, 7, 8, 13, 17, 18 and 24), extracellular matrix organization (CD206, TGM2 and MMP-1, -7, -9 and -12), T cell exhaustion (PD-L1) and angiogenesis (VEGFA, PDGFB, CHI3L1/2). PIMs expression was also detected in primary cHL-TAMs. To assess role of PIMs in TAMs, RS-M were treated with a dual pan-PIM/FLT3 inhibitor, MEN1703, and subjected to transcriptional, biochemical and immunophenotype analyses. MEN1703 skewed gene expression profiles of RS-M toward pro-inflammatory (M1) macrophages and downregulated expression of genes associated with pro-tumoral (M2) macrophages. Consistently, PIM inhibition in RS-M downregulated expression or decreased activity of M2-associated molecules (CREB1, AKT, STAT3/6, CD163, CD206, CD209), and decreased PD-L1 levels by 32%. PIM inhibition hampered important functions of RS-M, including their ability to promote angiogenesis, matrix remodelling (collagen uptake), and eosinophil recruitment. In direct cocultures, RS-M decreased activity of T lymphocytes. This suppressive effect was alleviated in cocultures with the PIM inhibitor-treated RS-M. Our data suggest that PIMs support pro-tumoral and immunosuppressive phenotype of cHL-TAMs. Since PIM activity is required for RS cell survival and immune escape, these kinases are rational targets for therapy in cHL. Grant support National Science Centre, Poland 2017/26/D/NZ5/00561 and 2016/22/M/NZ5/00668
T058: Safety and Dose-Expansion Study of Combination Favezelimab (anti–LAG-3) Plus Pembrolizumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Refractory to Anti–PD-1 Treatment
Authors: John Timmerman, David Lavie, Nathalie A. Johnson, Abraham Avigdor, Peter Borchmann, Charalambos Andreadis, Ali Bazargan, Gareth Gregory, Colm Keane, Inna Tzoran, Vladan Vucinic, Pier Luigi Zinzani, Hong Zhang, Pallavi Pillai, Akash Nahar, Alex F. Herrera
Journal: HemaSphere (2022)

Background: Optimizing therapies for pts with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 therapy failure remains of clinical interest. The multicohort phase 1/2 MK-4280–003 study (NCT03598608) evaluated the safety and efficacy of a LAG-3 inhibitor, favezelimab (MK-4280), + pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 2 focused on pts with R/R cHL after anti–PD-1 therapy. Methods: Part 1 was the safety lead-in phase to determine the recommended phase 2 dose (RP2D), followed by a dose-expansion phase (part 2). Eligible pts in cohort 2 had cHL and relapsed after or were ineligible for autologous stem cell transplantation and PD after ≥2 doses of anti–PD-1 therapy. Pts in part 1 received escalating doses (per mTPI design) of pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. In part 2, pts received pembro + favezelimab at RP2D for ≤35 cycles. Primary end point was safety. ORR was a secondary end point. DOR, PFS, and OS were exploratory end points. Database cutoff was March 21, 2022. Results: Part 1 identified 1 dose-limiting toxicity (DLT; autoimmune hepatitis [grade 4]) among the first 6 pts from all cohorts at the favezelimab 200 mg dose. No DLTs were found after an additional 15 pts at the 800 mg dose; RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. 34 pts were enrolled in cohort 2; median age was 37.5 y, 62% had ECOG PS 0, and 94% had ≥4 prior lines of therapy. At database cutoff, 22/34 pts had discontinued (11 PD; 7 AEs; 2 clinical progression; 2 pt withdrawal/physician decision); 18% discontinued due to treatment-related AEs (TRAE). No deaths were treatment related. 28 pts (82%) had TRAEs; most common (≥15%) were hypothyroidism (18%) and fatigue and nausea (15%, each); 6 pts (18%) had grade 3 or 4 TRAEs. After median follow-up of 18.4 mo, ORR was 30% (95% CI,16–49; CR, 3 [9%]; PR, 7 [21%]). 25/27 (93%) pts with a postdose scan had a baseline reduction in target lesions. 70% of responders had an anti–PD-1–based regimen as most recent line of therapy at study entry. Median DOR was 19.4 mo (range, 0+ to 19.4); 4 pts (65%) had response ≥12 mo. Median PFS was 9.4 mo (range, 5.1–14.7). and median OS was 25.7 mo (range, 21.2-NR). Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in pts with R/R cHL and PD following anti–PD-1 therapy. This combination shows potential to reinduce a response in this pt population.
P093: From involved- field to involved-node – Quality analysis of the radiation therapy in HD 17 by the expert panel of the German Hodgkin Study Group
Authors: Michael Oertel, Dominik Hering, Nina Nacke, Christopher Kittel, Kai Kröger, Jan Kriz, Michael Fuchs, Christian Baues, Dirk Vordermark, Rita Engenhart-Cabillic, Klaus Herfarth, Peter Lukas, Heinz Schmidberger, Simone Marnitz, Peter Borchmann, Andreas Engert, Uwe Haverkamp, Hans Theodor Eich
Journal: HemaSphere (2022)

Question: The use of radiotherapy (RT) for intermediate-stage Hodgkin lymphoma is discussed vividly. The HD17 trial of the German Hodgkin Study Group (GHSG) evaluated the value of consolidative involved-node (IN)RT for patients with PET-positivity after chemotherapy and enabled a comparison between INRT and involved-field (IF)RT [1]. The present work analyzes the quality of the performed RT. Methods/Material: For quality assessment, all INRT-plans in the HD 17 trial were requested and compared to a random selection of IFRT-cases in the standard arm. The RT was assessed by experts of the radiation therapy panel of the GHSG using initial (staging) imaging, RT plans and the recommendation forms by the reference radiation oncology. Evaluation was graded as „correct“, „minor deviation“ or „major deviation“. Statistical analyses were per-formed using a chi-square test in SPSS (version 27/28, IBM, NY, USA). Results: In total, 178 patients (INRT: 136, IFRT: 42) were analyzed, treated with a median RT dose of 30 Gy (IFRT: 18–30.6 Gy, INRT: 14 Gy-40 Gy). The majority (76.5 %) of INRT-cases showed no deviation compared to 69.1 % of IFRT-cases. Deviations were reported for 9.6 % and 14.0 % of patients in the INRT-group compared to 11.9 % and 19.1 % in the IFRT-group for minor and major deviations, respectively. There was no significant difference between both cohorts regarding the percentage of plans with deviations (p=0.333) or the percentage of major deviations (p=0.423). The principal causes for major deviations were too narrow target volumens in the involved region (IFRT: 6 vs. INRT: 1) or incorrect RT doses (IFRT: 1, INRT: 2). Conclusion: The performed INRT was delineated and planned correctly in most cases and reveals a high degree of quality. There has been no decline in RT-planning in comparison to IFRT. Continuous education is pivotal to enable high-quality INRT outside of clinical trials. Literature 1.Lancet Oncol. 2021 Feb;22(2):223-234.
T022: Sharing decisions regarding radiotherapy for Hodgkin lymphoma: a qualitative study of the experiences of patients and clinicians in the UK
Authors: Rebecca Shakir, Catriona Gilmour-Hamilton, Craig Bakin, Isabelle Gent, Adam Holloway, Alison Meeson, Johanna Ramroth, Georgios Ntentas, David Cutter, Michele Peters
Journal: HemaSphere (2022)

Figure 1: The radiotherapy decision-making process in current clinical practice, as described by patients and clinicians Background: Radiotherapy (RT) increases the chance of cure of Hodgkin lymphoma (HL) [1] but also has risks, including cardiac disease and second cancers [2]. Whilst guidelines broadly indicate which patients may benefit from RT, there are individual factors that can substantially affect the balance of benefit and risk. Little is known about how these factors are incorporated into decision-making, or patients’ preferences for involvement in decisions. This study aimed to explore the RT decision-making process, and better understand how patients’ preferences are taken into account. Methods: We conducted semi-structured interviews with 15 people treated for HL, and 12 clinicians who specialised in the treatment of HL. We used maximal variation sampling, and Braun and Clarke’s thematic analysis. The study was co-designed with four people previously treated for HL and approved by the North of Scotland Ethics Committee. Results: The decision about RT was commonly made by clinicians and presented to patients as a conclusion. Although patients acknowledged they could disagree with the clinicians’ recommendation, they often perceived themselves to be in a life-threatening situation with no real choice about treatment. Patients were highly engaged and keen to receive information, but the majority felt too overwhelmed by the complexity of their illness to participate in RT decisions. Patients and clinicians agreed that the ultimate responsibility for RT decisions lay with healthcare professionals, and that it was too challenging to lay the burden of this decision solely on the person with HL. Clinicians considered individual patient factors when recommending RT, and recognised the importance of ensuring that decisions were in line with a person’s values and preferences (Figure 1). Both patients and clinicians felt shared decision-making was hampered by the lack of easily accessible information predicting the risks of RT for an individual. Conclusion: Decisions about RT lay mostly with clinicians, but individual patient circumstances were considered. The availability of data to understand the risks of RT for an individual would enhance the decision-making process. Literature 1. Shaikh et al. Consolidation radiotherapy following positron emission tomography complete response in early-stage Hodgkin lymphoma: a meta-analysis. Leuk Lymphoma 2020;0:1 2. Gustavsson et al. A systematic overview of radiation therapy effects in Hodgkin’s lymphoma. Acta Oncol 2003;42:589
P090: Staging of Lung Lesions Survey Demonstrates Continued Need for Harmonization
Authors: Jennifer Seelisch, Sue C. Kaste, Kara M. Kelly, Lars Kurch, Michael P. Link, Christine Mauz-Koerholz, Kathleen Mccarten, Angela Punnett, Dietrich Stroevesandt, Jamie E. Flerlage
Journal: HemaSphere (2022)

Figure 1: Case vignettes and survey responses. Background: Staging of lung disease in Hodgkin lymphoma (HL) has been a longstanding and controversial challenge. In 1984, a survey of 14 experts was published in the Journal of Clinical Oncology. Four case vignettes were distributed, and experts designated each vignette as either Stage IIE or Stage IV disease. Results were very divided for 2 of the 4 case vignettes, and the conclusion was a call for clear guidance and group consensus for staging of lung lesions. Despite updates to the HL staging systems at both the Cotswold (1989) and Lugano (2014) meetings, there remains today, nearly 30 years later, a perceived lack of uniformity in the approach to the staging of lung lesions even among experts in the field. The approach to each of these issues not only varies across consortium groups but among individuals within the same consortium groups. When reviewing the most recent frontline HL trials from St. Jude-Stanford-Dana Farber, EuroNet PHL, and the Children’s Oncology Group, lung lesions were defined differently for each. This creates difficulty in comparing outcomes across trials and highlights the need for consensus and uniformity. Methods: The SEARCH for CAYAHL (Staging, Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult HL) group recreated a similar survey using 7 case vignettes and distributed it to 26 internationally recognized experts in pediatric HL to establish how current world experts are staging lung lesions (see Figure 1). Of the 21 survey respondents (81% response rate), 7 were radiologists or nuclear medicine radiologists, and 14 were pediatric oncologists. While there was near consensus for some of the cases, several remained very divided, namely around the role of PET avidity in lung lesions, the number and location of lung lesions, and the concept of contiguous disease. Conclusions: After reviewing the results of our survey, the SEARCH group acknowledges the controversy and inconsistency with which we are currently staging lung disease around the globe. We are now actively working to establish clear criteria, based on available data, and expert consensus through Delphi survey methods, and plan to have this completed in the fall of 2022.